Bortezomib is N-(2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid.

Solid bortezomib is not soluble at a concentration of 1 mg/ml in 0.9% w/v of sodium chloride. It is commercially available under the trade name of Velcade® for injection. It is given intravenously only and contains mannitol ester of bortezomib. It is available in a lyophilized form which when reconstituted forms a solution consisting of the mannitol ester in equilibrium with bortezomib. Velcade® is reconstituted with 0.9% sodium chloride to a final concentration of 1 mg/ml of bortezomib. The use of mannitol provides the desired solubility. The prescribing information (Physician Desk Reference, published by Thomson Healthcare, 62 edition, 2008, pp. 2151-2157) provides that the reconstituted product should be clear and colorless and should be visually inspected for particulate matter and discoloration and only clear solution which is not discolored should be used within eight hours after preparation. This guidance is in view of the extreme precautions required in administering drugs directly into the intravenous system. Formation of particles is undesirable and preparations should meet high purity requirements.
U.S. Pat. No. 6,713,446 describes that bortezomib is known to be stable for more than 2 years when stored at −2° C. to −20° C., as determined by HPLC analysis (purity>97%). But when stored at 2° C.-8° C., the product is not stable for longer than 3-6 months. U.S. Pat. No. 6,713,446 (hereinafter referred to '446) provides a stable, pharmaceutically acceptable composition comprising bortezomib. The claims of the patent encompass the commercially available Velcade® for injection. The inventors of the '446 patent have discovered that lyophilization of an aqueous mixture comprising a boronic acid compound and a compound having at least two hydroxyl groups provides a stable composition. The lyophilized material was readily soluble at concentration up to 6 mg/ml.
U.S. Pat. No. 6,617,317 (hereinafter referred to as patent '317) discloses a method for reducing the rate of degradation of proteins in an animal comprising contacting cells of the animal with certain boronic ester and acid compounds. Also disclosed are novel boronic ester and acid compounds, their synthesis and uses. The patent further discloses that the novel boronic ester and acid compounds can be converted to their basic salts by mixing a solution of a boronic acid (Z1 and Z2 are both OH) of the invention with a solution of a pharmaceutically acceptable non-toxic base, such as, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, or an amino compound, such as choline hydroxide, Tris, bis-Tris, N-methylglucamine or arginine. Water-soluble salts are preferable. The suitable salts that have been listed include: alkaline metal salts (sodium, potassium etc.), alkaline earth metal salts (magnesium, calcium etc.), ammonium salts and salts of pharmaceutically acceptable amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine and N-methyl-D-glucamine).
The chemical stability and stability problem of the parenteral formulation of Bortezomib has been reported in Sara Wu et al J. Pharm. Sci 89; 758-765, 2000 pp. 759-765). The reference indicates that the bortezomib showed erratic behaviour and was quite unstable in certain solvents. The authors also reported some observations on the effect of ascorbic acid and EDTA on its stability. Under acidic and basic conditions, it was observed that impurity D—an oxidative impurity was a major degradant. The article mentions that the degradation and pre-formulation studies of bortezomib was found to be quite complicated.
In attempts to prepare stable parenteral composition of bortezomib, the inventors of the present invention prepared solutions using various solubilizing agents. At a concentration of 1 mg bortezomib per ml, clear solution was obtained with certain solubilizing agents. Although a clear solution was obtained, it was observed that particles were rapidly formed in such solutions. In instances where the inventors had success in preventing particle formation, it was found that when the solutions were lyophilized, the lyophilized preparation was difficult to reconstitute into a ready clear aqueous solution. The inventors of the present invention have surprisingly discovered that these problems are resolved by preparing a composition comprising bortezomib and tromethamine with the pH adjusted in the range of 6.8 to 8.4. The inventors also identified that the problems of instability of the pharmaceutical composition in dry form as well as in a reconstituted form was connected to the impurity levels present in the bulk of the bortezomib. For instance, when bortezomib bulk with total impurity levels of about 3%, was used for preparing the injectable composition, the pH when adjusted to 7.6-8.4, the composition remained stable for desired period whereas when the bulk of bortezomib having total impurity levels less than 0.51% was utilized, the pH of the composition when adjusted to a pH of about 6.8-8.2, the composition remained stable for desired period.